Mechanisms of allergen-speci®c immunotherapy

Allergic diseases basically are immunologic disorders related to the activation of a distinct cytokine pattern in T cells, including increased secretion of certain allergic in ̄ammatory cytokines, particularly IL-4, IL5, and/or IL-13 (1±3). Whereas the symptoms of immediate and late-type allergic reactions can be ameliorated by various pharmacologic treatments, allergen-speci®c immunotherapy (SIT) represents the only curative approach for speci®c type I allergy (4±9). SIT is most ef®cient in allergy to insect venoms and allergic rhinitis (4±9). However, the mechanism by which SIT achieves clinical improvement remained unclear until recently. A rise in allergen-blocking IgG antibodies, particularly of the IgG4 class (10, 11), the generation of IgE-modulating CD8 T cells, and a reduction in the number of mast cells and eosinophils and release of mediators (12±14) were found to be associated with successful SIT. Furthermore, SIT was found to be associated with a decrease in IL-4 and IL-5 production by CD4 T cells, and, in some cases, with a shift toward increased IFN-c production (9, 15±22). However, it appeared that the induction of an unresponsive or anergic state in peripheral T cells and the reactivation of the response by cytokines from the tissue microenvironment are basic intermediate key steps in the mechanism of SIT (15±17). Thus, conditions of the immunologic microenvironment and production of cytokines by tissue cells may ®nally determine whether SIT will be successful or unsuccessful. Therefore, for successful and safe SIT, allergen variants should be created of which recognition sites for T cells remain intact, whereas binding sites for IgE antibodies are removed. Intact T-cell epitopes are required to enable the induction of speci®c T-cell tolerance or anergy against the antigen/ allergen. Not only are the antibody or B-cell epitopes a prerequisite for elicitation of adverse reactions, but IgE antibodies also focus the allergen ef®ciently onto antigen-presenting B cells, which present it to T cells in a way that favors development of a Th2-dominated cytokine pattern. A model especially suited for studies of human cellular and molecular mechanisms, regulating speci®c allergy and normal immunity provides the immune response to bee venom (BV) (15±19, 23±29). BV phospholipase A2 (PLA) represents the major antigen and allergen of BV, and SIT with whole BV (BV-SIT) or short PLA peptides representing immunodominant T-cell epitopes (PLA-PIT) was applied successfully.